The Silent "n" of PDUFA

• 05.13.2015

Statistics are like a bikini. What they show you are interesting, but what they conceal is essential.

Late last month the FDA’s Bioresearch Monitoring (“BIMO”) Program released its annual report on inspections from the previous fiscal year. 

In light of many key issues and initiatives, some of the results are, well … thought provoking.

For example:

·      Following well-publicized recalls of bioequivalent but therapeutically unacceptable generic versions of Budeprion and Metoprolol, the agency reported a 7% decrease in bioequivalence inspections (205 in FY13 and 190 in FY14). Something for the new Office of Pharmaceutical Quality to think about.

·      Can you say “Ranbaxy?” BIMO shows only paltry changes in international inspections from the drug side (CBER down 1 inspection – 24 in FY13 and 23 in FY14 and CDER up a dozen -- 202 in FY13 and 214 in FY14). It’s not the “n” it’s only the beginning.

With PDUFA reauthorization conversations getting under way, these and other metrics are going to be discussion starters and debate drivers. The complete report is worth a read.

Express Scripts CEO To Kids With Cystic Fibrosis: Find Another Way To Stay Alive

• 05.12.2015

Though medicines for cystic fibrosis are life saving,  insurers and pharmacy benefit managers force people with the disease to pay thousands of dollars out of pocket for them.  No new medicine has been approved for CF in nearly a decade.  Two years ago, one medicine called Kalydeco was approved.  It helps people with a specific genetic mutation causing their disease have been approved.  They are the only hope for the 2000 or so people with that mutation. 

Insurance companies and PBMs have responded by denying use of the drug altogether or forcing people to fail on other therapies or not covering the drug at all. 


 



The FDA is on the very of approving another medicine called Orkambi, which targets another rare mutation that causes CF patients to choke to death as their lungs fill up with mucus.   It will likely benefit another 4000 people.   And it will cost about $250K per patient per year.

This medical apartheid is justified by Steve Miller CEO of Express Scripts -- the biggest PBM in the US -- "we hope the product comes out at a more affordable price, because the burden to payers is extraordinary."

Except that it isn't.   The total market for CF drugs in the US is about $1.6 billion.  That's less than .001 percent of total health care spending.

Meanwhile Orkambi reduces pulmonary exacerbations.. which sounds nicer than it is.  They are described as a " period when lung disease worsens. This can include an infection, an increase in cough and sputum, a drop in lung function and weight loss. "

Exacerbations are linked to a higher risk of premature death, hospitalizations, and massive use of other medicines..all of which Orkambi would presumable prevent.  And the cost of an exacerbation can run into the hundreds of thousands.  That doesn't include the cost of lost productivity and reduced quality of life. 

So which is the bigger burden to payers and patients? 

But it appears that the PBMs and insurers don't care.  They will make Orkambi more expensive or  unavailable.

Such practices have been singled out as violating the civil rights of patients. As the Department of Health & Human Services has stated: “placing most or all drugs that treat a specific condition on the highest cost tiers discourages enrollment by individuals based on age or based on health conditions, in effect (is) making those plan designs discriminatory.”

Yet, insurers and PBMs have actually increased their redlining of the sick:  The number of plans engaging in discrimination has nearly doubled since 2012.  And this year they are charging 30 percent more for breakthrough medicines than they did in 2014.   PBMs are also increasing the number of medicines they won’t pay for at all by 35 percent.   Moreover, insurers are paying doctors bonuses to use cheaper drugs and not paying for medicines tailored to the specific ‘personality’ of their disease.

Woodcock WebEx on FDA's Office of Pharmacutical Quality

• 05.12.2015

Understanding CDER’s “Super” Office of Pharmaceutical Quality and Its Effect on You A One-On-One With FDA’s Dr. Janet Woodcock and Dr. Lawrence Yu

Wednesday, July 8, 2015  • 1:30 p.m. - 3:00 p.m. EDT Sign up now for this exclusive question-and-answer webinar with FDA veteran Peter Pitts, President and Co-founder of the Center for Medicine in the Public Interest, as he speaks with Dr. Janet Woodcock, Director of CDER and the driving force behind the formation of the OPQ and Dr. Lawrence Yu, Acting Director of CDER’s Office of Pharmaceutical Science, to help you understand all the changes that will effect you. They will discuss: Why this new super office was formed and what offices goals are How the formation will impact any pending business with the original eight offices Whether or not you’ll need to set up new contacts with regard to review or quality issues Are any changes coming to individual offices’ staffing or management? The latest on the search for a permanent director to lead the new office Plus, we set aside 30 minutes to give you the opportunity to have your own questions answered. This webinar is of particular importance to anyone who has had dealings with any of the following offices, which the OPQ now incorporates: Office of Program and Regulatory Operations (OPRO) Office of Policy for Pharmaceutical Quality (OPPQ) Office of Biotechnology Products (OBP) Office of New Drug Products (ONDP) Office of Lifecycle Drug Products (OLDP) Office of Testing and Research (OTR) Office of Process and Facilities (OPF) Office of Surveillance (OS)

Your Expert Presenters

Janet Woodcock, M.D., is director of the Center for Drug Evaluation and Research (CDER) and also serves as acting director of CDER’s Office of Pharmaceutical Quality (OPQ). A prominent FDA scientist and executive, Dr. Woodcock has received numerous awards, including a Presidential Rank Meritorious Executive Award, the American Medical Association's Nathan Davis Award, and Special Citations from FDA Commissioners. She joined FDA in 1986.

Dr. Lawrence X. Yu joined FDA in 1999 as a team leader in CDER’s Office of Pharmaceutical Science’s (OPS) Division of Product Quality Research, and was later promoted to deputy director in the Office of Generic Drugs. He currently serves as Acting Director, OPS, adjunct Professor of Pharmaceutical Engineering at the University of Michigan, and Associate Editor of AAPS J.

Peter Pitts is President and co-founder of the Center for Medicine in the Public Interest. Prior to founding CMPI, Pitts was a Senior Fellow for healthcare studies at the Pacific Research Institute. From 2002-2004 Peter was FDA’s Associate Commissioner for External Relations, serving as senior communications and policy adviser to the Commissioner. He supervised FDA's Office of Public Affairs, Office of the Ombudsman, Office of Special Health Issues, Office of Executive Secretariat, and Advisory Committee Oversight and Management.

Webinar Details

When?  Wednesday, July 8, 2015

Time? 1:30 p.m. – 3:00 p.m. EDT

There’s just one low registration fee per site regardless of how many participate. Generous multi-site discounts are available, too. Simply call (888) 838-5578 in the U.S. or +1 (703) 538-7600 globally.

PDUFA Jr. funding theory DOA

• 05.09.2015

The U.S. House Energy & Commerce Committee staff have asked the Pharmaceutical Research and Manufacturers of America (PhRMA) and the Biotechnology Industry Organization (BIO) to offset some or all of the cost of the proposed 21st Century Cures Act, according to individuals involved in the discussions.

According to a report in BioCentury The trade associations adamantly refused to consider the proposal in a conversation with E&C staff this week.


A discussion draft of the legislation released last week included $10 billion over five years to create an “Innovation Fund” at NIH. The draft employed unusual language to bypass the standard funding process, avoiding the need for approval by House and Senate appropriations committees.
E&C Chairman Rep. Fred Upton (R-Mich.) has said the bill will be fully paid for, which means the committee will have to find revenue or savings to cover its costs and make the bill budget-neutral.


Industry objects to paying for the 21st Century Cures Act because companies feel the current discussion draft contains few provisions that would benefit them. Provisions in the first discussion draft that would have provided generous additional market exclusivity for many drugs were stripped out due to objections from Democrats.

Per BioCentury, Biopharma companies are also disappointed by language in the draft on biomarker qualification, a top priority for industry, because it codifies current FDA practice and is unlikely to increase the number of qualified biomarkers.
Companies also do not want to set a precedent for industry funding of NIH. Industry is already paying directly for numerous FDA programs through user fees, and will certainly be asked to increase its contributions to cover the cost of the Breakthrough Therapies program in PDUFA reauthorization negotiations.

The other kind of fair balance and adequate provision

• 05.09.2015

In response to a May 4, 2015 story in the New York Times about Essure permanent birth control, Bayer submitted the following letter to the editor, which the New York Times refused to publish in its entirety.

The Gray Lady’s space considerations notwithstanding, this is an issue of both fairness and accuracy.

To the Editor:

Re: “Long-Term Data on Complications Adds to Criticism of Contraceptive Implant” (May 4, 2015), Roni Rabin mischaracterizes a recently published long term study on Essure. This well-designed, well-executed study reinforces the safety and efficacy of the device and the procedure. The side effects reported are consistent with numerous other scientific studies and the Instructions for Use on Essure – which the FDA approved in 2002 and then reevaluated in 2013.   

Women deserve access to a wide range of contraceptive options, and Essure is an important non-surgical and non-hormonal option for women who have completed their families and want permanent birth control. However, no medical device, procedure, or even drug is completely free of side effects.

That's why the importance of the conversation between patients and their doctors cannot be overstated. Health professionals must appropriately counsel their patients about Essure, and women who experience any issues should immediately contact their OBGYN.

Moreover, while social media is a valuable tool for patient support, it should never be used as a substitute for medical advice from an experienced, board certified physician. Bayer has reached out to many women on social media who have said they’ve experienced problems with Essure, and we encourage any woman who has concerns to contact us at uswomenshealth@bayer.com or 1-888-84BAYER so we can help her get the support she needs.

Regards,

Philip Blake
President, Bayer Corporation

Something fishy in the off-label conversation

• 05.08.2015

Unless the FDA takes control of the off-label conversation firmly and swiftly. Things are not going to be pretty.

Case in point -– a company jumping on the off-label bandwagon because of an FDA decision they didn’t like? Dangerous times.

Here’s the brief from the Wall Street Journal:

Drug firms challenge FDA over free speech

To what extent should drug makers be allowed to distribute information about unapproved uses for their medicines?

The question has been widely debated after a federal appeals court three years ago overturned the criminal conviction of a sales rep for promoting so-called off-label uses of a drug. The court ruled his actions constituted protected speech, since the information was truthful and not misleading.

Since then, the pharmaceutical industry has been lobbying the FDA to revise its guidelines, because the decision only applied to three states. The agency hasn't indicated when it will take action, but plans to hold a meeting this summer to review the topic.

Now, one drug maker is trying to force the issue. Amarin Corp. on Thursday filed a lawsuit hoping to convince a federal court that the FDA prohibition on off-label promotion violates the company’s First Amendment rights, and that its reps should be able to convey truthful and “non-misleading” information to doctors.

“It’s important the FDA does not have the power to stifle speech,” said Floyd Abrams, a constitutional lawyer who represents Amarin. “And FDA is effectively stifling speech, unless we get a firm ruling from a court, which is very important to ensure the public is well served.”

Amarin took action after growing frustrated with an FDA decision about its Vascepa prescription fish-oil pill. The medicine is approved to treat people with very high levels of triglycerides, a type of fat in the blood that can lead to heart disease, but Amarin sought to sell the drug to people with lower levels.

Late last month, the agency rejected that request and also decided Amarin couldn't include clinical trial data in Vascepa labeling about the extent to which the pill may effectively treat people with slightly lower levels of triglycerides. Data from the trial is in the labeling.

As far as Amarin is concerned, it now “finds itself in a bind,” according to its lawsuit in federal court in New York. The drug maker “may not freely communicate truthful and nonmisleading information about Vascepa to health-care professionals…without fear of criminal prosecution and civil liability.”

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“This is a very big deal,” said Ira Loss, senior health-care analyst at Washington Analysis, a consulting firm. “If the court rules they can disseminate information as they would like to do so, It would open things up for much more promotional activity of pharmaceutical products.”

To what extent Amarin will be successful remains unclear. But the case is going to be very closely watched because it has the potential to dramatically shift the way the pharmaceutical industry markets medicines and interacts with physicians.

This “could bring to a head a lot of the issues we’ve all been talking about for a number of years,” said Alan Bennett, a lawyer who represents the Medical Information Working Group, several drug makers that petitioned the FDA to move faster to issue new guidelines about conveying off-label information.

But some worry a ruling that favors Amarin will weaken protections for patients. “This will undermine the drug-approval process and allow companies to bypass the FDA,” said Michael Carome, who heads Public Citizen Research Group. “There would be no incentive to seek FDA approval for new uses.”

The lawsuit, meanwhile, adds pressure on the FDA to move faster to issue guidelines. “It’s always better for the agency to control the pace,” said Peter Pitts, a former FDA associate commissioner for external affairs, who now does policy consulting for the pharmaceutical industry.

Off Label Communications gets a Buzz Cut

• 05.07.2015

A somewhat slanted viewpoint on off-label communication? You be the judge.

Under pressure, FDA to hold public meeting on off-label use

By Toni Clarke

May 6 (Reuters) - The U.S. Food and Drug Administration will hold a public meeting this summer to address drug company concern that restrictions on what they can say about off-label use of drugs violate their First Amendment right to free speech.

The meeting, announced last month by FDA chief counsel Elizabeth Dickinson, comes as a bill known as 21st Century Cures, designed to speed new drugs to market, is moving through Congress. Language in the bill is adding pressure on the agency to relax its guidelines.

Efforts by drug companies to change the rules gained steam after a 2012 decision from the Second Circuit Court of Appeals, which overturned the conviction of Alfred Caronia, a sales representative for Orphan Medical, which was later acquired by Jazz Pharmaceuticals Inc. After Caronia was caught talking to physicians about various off-label uses of the narcolepsy drug Xyrem, the court said the First Amendment protected truthful and non-misleading off-label speech.

Under current rules, physicians are allowed to prescribe medicines off-label for whatever condition they want. But drug companies are not allowed to promote them for uses that have not been approved by the FDA.

Pharmaceutical companies are citing the Caronia and similar rulings to pressure the FDA to let them talk more freely about off-label use.

"If you're a community physician it's hard to stay current," said Coleen Klasmeier, a partner at Sidley Austin LLP, which petitioned the on behalf of a coalition of pharmaceutical companies to "adequately justify and appropriately tailor its regulatory regime" in light of Caronia and similar rulings.

The coalition, known as the Medical Information Working Group, includes Pfizer Inc, Sanofi, Novartis AG, Johnson & Johnson, Eli Lilly and Co and GlaxoSmithKline Plc, among others.

At stake are billions of dollars in potential sales if manufacturers can persuade physicians to use their products for unapproved uses and a potentially significant weakening of the FDA's regulatory authority.

Karen Riley, an FDA spokeswoman, said the agency decided to hold a public meeting "because of the wide range of views held by different stakeholders and the importance of the underlying public health issues."

OFF-LABEL PROMOTION

Drug companies have a long history of breaching the off-label rules. Over the past decade 17 companies paid more than $16 billion in settlements for off-label promotion, according to the American Medical Association, including Pfizer, GlaxoSmithKline and Eli Lilly.

In September, Shire Plc agreed to pay $56.5 million to settle charges it overstated the benefits of its attention deficit disorder drug Adderall XR and claimed, with little evidence, that it would prevent criminal behavior, traffic accidents and sexually transmitted disease.

"At my own medical center we have banned pharmaceutical reps from coming because we don't think they are a good source of information," said Dr. Rita Redberg, professor of medicine at the University of California, San Francisco, and editor of the medical journal JAMA Internal Medicine. "You don't ask the barber if you need a haircut."

Off-label use already accounts for 10 percent to 20 percent of prescribing, with that figure rising in oncology and pediatric rare diseases, according to the AMA, which said it "supports the important need for physicians to have access to accurate and unbiased information about off-label uses of drugs and devices, while ensuring that manufacturer-sponsored promotions remain under FDA regulation."

REPUTABLE JOURNALS

The FDA does allow companies to provide doctors with data from well-controlled clinical trials from reputable medical journals and reference texts (but not from early clinical trials or letters to editors) and they can talk about off-label use at medical conferences. They can also respond to unsolicited questions from physicians as long as the responses do not tout the benefits of a product without disclosing its risks.

Companies want to be able to discuss data that does not come from randomized clinical trials. They also want to be able to provide economic analyses to insurance companies showing why a drug should be covered.

"Let's say a drug is very expensive and very effective and doesn't have many side effects," Klasmeier said. "If you're a health plan and you are trying to decide whether to pay for the drug you want to know how it stacks up against others."

Industry pressure has "forced the FDA to think harder about this topic," said Peter Pitts, a former FDA associate commissioner for external relations, who is now president of the Center for Medicine in the Public Interest, a think-tank that receives funding from drug companies.

In response to petitions from the coalition, the FDA noted that its regulatory framework was developed "in response to public health tragedies" but said it "recognized the evolving legal landscape in the area of the First Amendment" and promised to review its policies.

It has proposed adding clinical practice guidelines to the list of material companies can circulate. These are often developed by professional associations and may include treatment and dosing regimens that differ from what is on a drug's label.

It has also proposed allowing companies to distribute medical literature showing a product's side effects to be less than described in the label. Comments from the public in response to the proposal were overwhelmingly opposed, according to documents obtained and made public by the consumer watchdog Public Citizen.

TRUTHFUL BUT NOT MEANINGFUL

Those moves have not been enough to appease the industry. Yet public health advocates fear that if the FDA yields further, companies may be able to circulate data which is truthful under the Caronia definition without being meaningful for patient health.

A 2012 study showed that up to 75 percent of published preclinical trial results could not be reproduced in subsequent trials. An earlier one showed that when scientists attempted to corroborate 34 claims from frequently cited published trials they were unable to do so 41 percent of the time.

"People do not realize that the consequences of this new ideological approach to the First Amendment will be measured in lives," Dr. Joshua Sharfstein, a former principal deputy commissioner at the FDA who is now associate dean at Johns Hopkins Bloomberg School of Public Health.

For example, doctors prescribed schizophrenia and bipolar disorder drugs for years to control behavior in elderly patients with dementia. Studies later showed they increased the rate of death in the elderly.

Premarin and Prempro, drugs to treat symptoms of menopause, were prescribed extensively to women for years on the assumption they would prevent increased coronary disease. The hypothesis was supported by some data but not by randomized, controlled clinical trials. When the drugs were eventually analyzed in a large government-sponsored trial they were found to increase the risk of stroke and heart attack.

If companies can market drugs for off-label uses there will be no incentive for them to conduct the clinical trials needed to show the products work and are safe, critics say.

"If off-label marketing is allowed then drugs will come to be used for a wide variety of conditions for which there has not been developed evidence of safety and efficacy," said Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. "You take away those checks and balances and it's the wild, wild west."

Seeking Clarity on Complexity

• 05.06.2015

From this morning's edition of Morning Consult ...

Seeking Clarity on Complexity

A new bill introduced by Rep. Michael Burgess (R-Texas), the Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015 (H.R. 1576), is an effort to get ahead of the curve on complexity. Rep. Burgess’ legislation would have the Government Accountability Office (GAO) study some of the unique challenges presented by the Food and Drug Administrations’s evaluation of generic versions of complex drug products. These challenges are as important to serving the public health as they are complicated when it comes to regulation.

A Little 21st Century Cures Rah Rah

• 05.06.2015

May 05, 2015, 02:00 pm

Congress must encourage the 21st Century Cures Initiative

By Peter J. Pitts

Over 200,000 American heart attack survivors will have another heart attack this year. Fortunately, the FDA recently approved Zontivity -- a medicine that prevents blood clots in people who have already suffered a heart attack. In clinical trials, the new drug significantly reduced the rate at which survivors experience another heart attack.

But this breakthrough came too late for the nearly 5 million Americans who died of heart disease during the eight years between when Zontivity first proved effective in clinical trials and when the FDA granted approval.

Times have changed. The "gold standard" of large-scale, long-term, and expensive clinical trials requires reinvention. That's why Congress should encourage the 21st Century Cures Initiative. Though still a work in progress, the bipartisan congressional initiative has the potential to streamline the drug approval process -- delivering breakthrough treatments to patients sooner and eliminating wasteful spending.

More efficient regulations could free up billions for new research and development. That's why the 21st Century Cures Initiative is proposing measures that accelerate the approval process by reducing "regulatory duplication and unnecessary delays."

The initiative's proposals could help to revolutionize the current drug approval process. Today, pharmaceutical companies test thousands of compounds in the lab until they identify one that shows promising medical applications. Next, they conduct "phase I" trials on healthy adult males to ensure a drug is safe.

Phase II trials provide an initial assessment of a drug's effectiveness in sick patients. Phase III, which involves thousands of volunteer patients, helps confirm the results of phase II trials. 

The draft legislation will allow FDA regulators to approve a groundbreaking drug if it proves effective after a phase II trial. That will deliver treatments to patients much sooner and eliminate the need for some phase III trials, which take years and account for 90 percent of the total development costs for drugs that eventually gain FDA approval. 

Had the law been in effect in 2007 when Zontivity passed its phase II trials, millions of patients could potentially have accessed the new treatment. Instead, barely 10,000 people received the drug during years of phase III trials. 

The 21st Century Cures Initiative will also spur new drug development by helping biotech companies "fail faster." Of all the potential medicines that enter phase I trials, only 8 percent ever receive FDA approval. The proposed legislation would expedite "adaptive clinical trials" which identify the failures -- the other 92 percent -- earlier. That prevents researchers from wasting time and money on drugs that ultimately don't pan out.

Identifying and scrapping those failures earlier in the research and development process will allow drug companies to redirect billions towards more promising treatments. If adaptive clinical trials can catch even 5 percent of eventual failures in phase I instead of phase III, pharmaceutical manufacturers will save at least $15 million per drug.

The proposed changes mark the beginning of a transition towards a true 21st century innovation system that eliminates traditional phase II and III trials altogether. In such a system, doctors, insurers, and drug makers could use the power of big data to chart a drug's effectiveness and patient outcomes as soon as it proves safe in phase I trials. Using crowd-sourced, real world data will deliver lifesaving treatments to patients years quicker than the current clinical trial process.

Congress should ensure that Americans have the best and latest drugs possible as quickly as possible. Passing the 21st Century Cures Initiative is the best way to do so.  

Pitts, a former FDA associate commissioner, is president of the Center for Medicine in the Public Interest.
 

The Gray Lady & the Non-Interference Clause

• 05.05.2015

To the Editor:

Allowing the Federal government to negotiate drug prices (Runaway Drug Prices, May 5, 2015) would result in prices going up and patient choice going down. That’s why the Non-Interference Clause, the legislation that prohibits Federal price negotiation was created in the first place. It’s interesting and important to note that the legislative language was drafted by Senators Ted Kennedy and Tom Daschle.

Is there a need to negotiate Medicare drug prices? The Congressional Budget Office found that between 2004 and 2013, Part D will cost an extraordinary 45 percent less than what was initially estimated and premiums for the program are roughly half of the government’s original projections.

These unprecedented results are largely due to Part D’s market-based structure. Beneficiaries are free to choose from a slate of private drug coverage plans, forcing insurers to compete to offer the best options to American seniors. It’s hardly surprising that the program has led to low prices and satisfied customers.

Through their own negotiations with drugmakers, private insurance plans that operate under Part D have already had great success in keeping pharmaceutical prices down. In fact, the CBO has observed that Part D plans have “secured rebates somewhat larger than the average rebates observed in commercial health plans.”

What’s more, the CBO has said that doing away with the non-interference clause “would have a negligible effect on federal spending.” In a report from 2009, they reiterated this view, explaining that such a reform would “have little, if any, effect on [drug] prices.”

In fact, allowing the feds to negotiate drug prices under Part D would likely have a negative effect on the program. The CBO predicts that when HHS forces pharmaceutical firms to lower the cost of a particular drug, this tactic brings with it “the threat of not allowing that drug to be prescribed.”

Senators Kennedy and Daschle knew what they were talking about. The President should pay close attention.

Peter J. Pitts

Pitts, a former FDA Associate Commissioner, is President of the Center for Medicine in the Public Interest